Overview

The endocrine system—the other communication system in the body—is made up of endocrine glands that produce hormones, chemical substances released into the bloodstream to guide processes such as metabolism, growth, and sexual development. Hormones are also involved in regulating emotional life.

Thyroid gland

The thyroid gland secretes thyroxin, a hormone that can reduce concentration and lead to irritability when the thyroid is overactive and cause drowsiness and a sluggish metabolism when the thyroid is underactive.

Parathyroid glands

Near the thyroid are 4 tiny pea-shaped organs, the parathyroids, which secrete parathormone to control and balance the levels of calcium and phosphate in the blood and tissue fluids. This, in turn, affects the excitability of the nervous system.

Pineal gland

The pineal gland is a pea-sized gland that apparently responds to exposure to light and regulates activity levels over the course of the day.

Pancreas

The pancreas lies in the curve of the duodenum and controls the level of sugar in the blood by secreting insulin and glucagon.

Pituitary gland

The pituitary gland produces the largest number of different hormones and, therefore, has the widest range of effects on the body's functions. The posterior pituitary is controlled by the nervous system. It produces 2 hormones: vasopressin, which causes blood pressure to rise and regulates the amount of water in the body's cells, and oxytocin, which causes the uterus to contract during childbirth and lactation to begin. The anterior pituitary, often called the "master gland," responds to chemical messages from the bloodstream to produce numerous hormones that trigger the action of other endocrine glands.

Gonads

These reproductive glands—the testes in males and the ovaries in females, and, to a lesser extent, the suprarenal (adrenal) glands —secrete androgens (including testosterone) and estrogens.

Suprarenal (adrenal) glands

The 2 suprarenal glands are located above the kidneys. Each has 2 parts: an outer covering, the adrenal cortex, and an inner core, the adrenal medulla. Both influence the body's responses to stress. For example, in response to a stressful situation, the pituitary gland may release beta endorphin and ACTH, which, in turn, prompt the suprarenal cortex to release hormones. Meanwhile, the autonomic nervous system stimulates the suprarenal medulla to secrete hormones such as epinephrine into the bloodstream.

See the image below.

Suprarenal (adrenal) gland, anterior view.

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Gross Anatomy

Brief history of endocrinology

The concept of neurosecretion was first elucidated by Ernst Scharrer and colleagues in the 1930s on the basis of the morphologic study of the hypothalamus of fish and mammals. Seventeenth-century English anatomist William Harvey, who questioned some of Galen's conclusions, described the heart as a 4-chambered pump that moves blood through arteries and veins, not air.

In 1849, Berthold transplanted testes from normal cocks to capons and cocklike feathers reappeared. Addison recognized the relationship between low blood pressure, muscular weakness, weight loss, bronzing of skin, and the pathology of the suprarenal gland in 1855. In 1871, Hilton-Fagge related the cretinoid state to a congenital inadequacy of thyroid function in early childhood. Eight years later, Gull related dry skin, sparse hair, puffiness of the face and hands, and a swollen tongue to myxedema, the pathological deficiency of thyroid function in adults (goiter). In 1902, Balysis and Startling extracted and identified the first hormone secretin (secreted by cells in the intestinal mucosa), and, in 1927, McGee isolated and purified substances that were androgenic in small amounts (microgram levels). He used a bioassay to test his substance. He applied it to the beak of sparrows, and the beak darkened.

Introduction

The endocrine system consists of endocrine glands that produce and secrete hormones into the blood stream to reach and act on target cells of specific organs. These hormones regulate the body's growth, and are involved in cell to cell communication, control metabolic activity, sleep-wake homeostasis, and altered regulation or dysregulation of adaptive response in various physiologic and pathophysiologic states. The hormones are released into the bloodstream and may affect one or several organs throughout the body.

The concept of endocrine function thus was expanded to paracrine, autocrine, juxtacrine, and intracrine functions, whereas the classic endocrine system included the traditional endocrine axes. The major glands of the endocrine system are the hypothalamus, pituitary, thyroid, parathyroids, suprarenals, pineal body, and the reproductive organs (ovaries and testes). The pancreas is also a part of this system; it has a role in hormone production as well as in digestion. Our life exists through maintenance of a complex dynamic homeostasis or equilibrium, which changes constantly by intrinsic or extrinsic factors or stressors. Thus, stress is defined as threatened homeostasis that is established by physiologic and behavioral adaptive responses of the organism.
[1]

The endocrine system is regulated by feedback in much the same way that a thermostat regulates the temperature in a room. For the hormones that are regulated by the pituitary gland, a signal is sent from the hypothalamus to the pituitary gland in the form of a "releasing hormone," which stimulates the pituitary to secrete a "stimulating hormone" into circulation. The stimulating hormone then signals the target gland to secrete its hormone. As the level of this hormone rises in the circulation, the hypothalamus and the pituitary gland shut down secretion of the releasing hormone and the stimulating hormone, which in turn slows the secretion by the target gland. This system results in stable blood concentrations of the hormones that are regulated by the pituitary gland.

The immune system is the third integrative system maintaining homeostasis. Endocrine and neural factors influence the immune response, and, in turn, cytokines—the secretions of lymphocytes, monocytes, and vascular elements—modulate both endocrine and neural functions. The immune system is a communication network that recognizes foreign antigens such as bacterial toxins and fungi and secretes signaling cytokines that regulate brain, endocrine, and immunocyte function. Virtually all endocrine changes involved in the adaptation of the stress, regulation of reproduction and homeostasis are integrated with specific behaviors.
[2]

Pituitary gland lies in the base of the skull in a portion of sphenoid bone and consists of an anterior lobe (adenohypophysis) and a posterior lobe (neurohypophysis). The size of the gland, of which the anterior lobe consists of two thirds, varies considerably. It measures 13x9x6 mm and weighs approximately 100 mg. It may double in size during pregnancy.

Superiorly, the pituitary gland is covered by diaphragma sellae, or sellar diaphragm. The diaphragma sellae has a 5-mm wide central opening that is penetrated by the hypophyseal stalk. Embryologically, the pituitary gland originates from 2 distinct places. Rathke's pouch, a diverticulum of the primitive oral cavity (ectoderm), gives rise to the adenohypophysis. The neurohypophysis originates in the neural ectoderm of the floor of the forebrain. Pituitary function is regulated by 3 interacting elements-hypothalamic neurosecretions, so-called releasing factors, feedback effects of circulating hormones, and autocrine and paracrine secretions of pituitary itself.

The neurohypophysis includes the neural tube, the neural stalk, and the specialized tissue at the base of the hypothalamus through which the neurons of the neurohypophysis pass. The superficial plexus gives rise to hairpin-like capillary loops that penetrate the median eminence. The base of the hypothalamus contains the nerve terminals of neurons that secrete the hypophysiotrophic factors and specialized blood vessels that convey these secretions to the anterior pituitary. The base of the hypothalamus forms a mound called the tuber cinereum. Blood from the capillary plexus returns to the portal vein that enters the vascular pool of the pituitary. The major nerve tracts of the neurohypophysis arise from relatively large-celled paired nuclei—the supraoptic nucleus is located above the optic tract, and the paraventricular nucleus is located on the each side of third ventricle.

The paraventricular nucleus secretes AVP (arginine vasopressin), also called antidiuretic hormone (ADH), which regulates the water conservation by the kidney, and it secretes oxytocin, which acts on the uterus and breast. Oxytocin are formed in cells in the hypothalamus, transported to the neural lobe by axoplasmic flow, and released into the blood as hormone to regulate organ function at remote sites. Neurotransmitters are released into the synaptic cleft and stimulate (or inhibit) postsynaptic neurons. Vasopressin-containing fibers are distributed wildly within the neuraxis and neural tube. Some of major nerve fibers terminate to the median eminence, which is partially controlled by anterior lobe.

Histology of the pituitary gland

Anterior pituitary cells were originally classified as acidophil cells, basophil cells, and chromophore cells. Researchers using immunocytochemical and electron microscopic techniques classified cells by their secretary products, as follows:

Acromegaly: Progressive coarsening of facial features (excessive secretion of GH in adult)

Gigantism (GH excess)

Dwarfism (GH deficiency)

ACTH

Cushing disease (excess)

Addison disease (deficit)

TSH

Hypothyroidism

Secondary thyrotoxicosis

LH/FSH

Nonfunctional pituitary tumor

Prolactin (PRL)

Prolactinemia (excess)

Pituitary-adrenal axis: corticotrophin-releasing hormone (CRH)

Corticotropin releasing hormone is a 41-amino acid peptide and the principal hypothalamic regulator of the pituitary-adrenal axis.
[3] CRH and CRH receptors were found in many extrahypothalamic sites of the brain including the limbic system and sympathetic system in brain stem and spinal cord. CRH is also found in the lung, liver, and gastrointestinal tract. CRH acts by binding to specific receptors.
[4] Human CRH differs from the ovine sequence by 7 amino acids. Human and rat CRH are identical.

The normal value of secretion of cortisol is range from 22-69 micrograms per 24 hours. The central neurochemical circuitry is responsible for activation of the stress system. Reciprocal neural connections exist between nonadrenergic neurons and the CRH of the central stress system.
[5, 6, 7, 8, 9, 10, 11]

CRH and catecholaminergic neurons also receive stimulatory innervation from the serotonergic and cholinergic systems. CRH released into the hypophysial portal system is a principal regulator of the anterior pituitary corticotroph-adrenocorticotropic hormone (ACTH). The autonomic nervous system responds rapidly to stressors and the neurotransmitters acetylcholine and norepinephrine, which affects both on the sympathetic and parasympathetic subdivisions of the autonomic nerve system.
[12] CRH has also shown to partly mediate the pyogenic effects of the inflammatory cytokines-IL-1, tumor necrotic factor, and IL-6.
[13]

Thyroid axis: thyrotropin-releasing hormone (TRH)

TRH is a tripeptide. Although the TRH tripeptide is the only established hormone encoded within its large prohormone, other sequences may have biologic function. TRH mRNA and TRH prohormone are present in several types of neurons that do not express TRH. In normal individuals, TRH activation of the HPA axis is associated with decreased thyroid-stimulating hormone (TSH).

Inhibition of TSH secretion might also participate in the central components of thyroid axis suppression during stress. During the stress, inhibition of TSH secretion and enhancement of somatostatin production may occur, in part through direct effect on inflammation cytokines on the hypothalamus, pituitary, or both.

The thyroid is the largest of the endocrine organs, weighting approximately 15-20 g. Two pairs of vessels constitute the major arterial blood supply. Namely, the superior thyroid artery, arising from the external carotid artery, and the inferior thyroid artery, arising from the subclavian artery via the thyrocervical trunk. Estimated blood flow range from 4-6 mL/min/g. The thyroid is innervated by both adrenergic and cholinergic nervous system via cervical ganglia and vagus nerve.

Regarding vasomotor innervation, a network of adrenergic fibers terminate near the basement membrane of the follicle. The gland is composed of closely packed sacs, called acini or follicles, which are invested with a rich capillary network. Thyroid cells express the TSH from the pituitary thyrotropes. The regulation of TSH secretion by thyroid hormones is TSH receptor, a member of the G-protein-coupled receptor family. The metabolic transportation of thyroid hormone in peripheral tissues determine their biologic potency and regulate their biologic effects. A wide variety of iodothyronines and their metabolite exist in plasma. T4 is the highest in concentration and the only one that arises solely from direct secretion by the thyroid gland. T3 is also released from the thyroid but most plasma T3 is derived from the peripheral tissues by the enzymatic removal of a single iodine from T4.

Abnormalities of thyroid gland

Hyperthyroidism: excess level of T4 (Graves disease)

Hypothyroidism: deficit of T4 with high level of TSH- (Hashimoto thyroiditis)

Growth hormone (GH) and insulin-like growth factor (IGF)

Growth axis

Growth is a common to all multicellular organisms and occurs by cell replication and enlargement along with nonhomogeneous processes of cell and cell organ differentiation. Human GH is produced as a single chain, 191-aminoacid, 22kd protein.
[14, 15] It is not glycated but contains 2 intramolecular disulfide bonds. Normally, about 97% of GH is produced by the pituitary gland. GH secretions largely reflect the 2 hypothalamic regulatory peptides. GH-releasing hormone (GHRH) and somatostatin. GHRH is species specific. Somatostatin appears to affect the timing and amplitude of pulsatile GH secretion rather than to regulate synthesis. The regulation of the reciprocal secretion of GHRH and somatostatin is imperfectly understood.

Multiple neurotransmitters and neuropeptides are involved including, serotonin, histamine, norepinephrine, dopamine, acetyl choline, gastrin, gamma butyric acid, thyroid-releasing hormone, vasoactive intestinal peptide, gastrin, neurotensin, substance P, calcitonin, neuropeptide Y, vasopressin, and corticotropin-releasing hormone. Lately, attention has been focused on galanin, a 29 amino-acid peptide found in the hypothalamus that is capable of both directly stimulating GH release and the GH secretory response to GHRH.
[16] The synthesis and secretion of GH are also regulated by the insulinlike growth factor (IGF) peptides.
[16, 17, 18] The growth axis is also inhibited at many levels during stress. Prolonged activation of the HPA axis leads to the suppression of growth hormone. GH secretion is markedly stimulated during the slow wave sleep.
[19, 20, 21]

Gonadal axis

The pituitary gonadotroph (influencing primarily the secretion of luteinizing hormone (LH), and the gonads and render target tissues of sex steroids resistant to these hormones.
[24, 25] In the presence of normally functioning hypothalamus, LH, FSH secretion by the pituitaries of both sexes is supported by constant dosage of androgens and estrogens. Negative feedback effects are mediated at the level of both the brain and pituitary gland.

If hypothalamic control is inactivated, basal gonadotropin secretion falls and the hypersecretory response to castration is blunted or abolished. LHRH neurons do not contain estrogen receptors. The steroid regulatory inputs from the gonads are neural influences on the secretion of LHRH derived from several parts of the brain. An intrinsic pulse generator is located in the arcuate nucleus. LHRH neurons also receive important inhibitory neural signals that mediate stress-induced gonadotropin secretion.

Men

In young adult men, 24-hour profiles of circulating luteinizing hormone (LH) exhibit episodic pulses, which appears to be temporally related to the REM-non REM cycle during the sleep period. Circulation variations of circulating FSH and LH levels are either low or undetectable.
[26] In contrast, a marked diurnal rhythm in circulatory testosterone and superimposed on episodic pulse. The maximal level of testosterone in the early morning and low level in the evening
[27] and is likely due to suprarenal androgen secretion. Nocturnal LH and testosterone levels are also blunted in patients with obstructive sleep apnea. Aging is associated with a progressive decline in testosterone levels after 30 years old while sex hormone-binding globulin levels increase.
[28] The decline in testosterone secretion appears to be primarily attributable to partial testicular failure.

Women

Puberty does not begin until the onset of pulsatile LHRH secretion by the hypothalamus.
[29] The magnitude of the pulses progressively increase throughout the puberty as estrogen levels increase. Thus, it controls the time of puberty. During the menstrual cycle, the complicated changes in gonadotropin secretion. The finding suggests that the feedback effects of gonadal steroids and peptides occur predominantly at the pituitary level. In pubescent girls, the sleep period is associated with an increase in LH and FSH pulse amplitude. On the contrary, in adult woman, sleep is always associated with an inhibition of LH secretion. Highest durations of non-REM sleep (primarily stage II) were found in late follicular phase and in early luteal phase than during follicular phase. The gonadotropic function in menopause women declines and estrogen and progesterone levels are declining.

At menopause, ovarian steroid production falls dramatically and in postmenopausal women, estradiol, progesterone, and androgen levels are very low. Central opioidergic neurons tonically suppress LHRH secretion except during the ovulatory surge when they are inhibited.

New data may be expected on the effect of endocrine disruptors on steroid hormone binding to selective plasma transport proteins, namely transcortin and sex hormone–binding globulin. Endocrine disruptors interfere with steroid biosynthesis and metabolism, either as inhibitors of relevant enzymes or at the level of their expression.
[30]

During the follicular phase in adult women and men, an LHRH pulse occurs approximately every 90-120 minutes throughout the day. Changes in the frequency and amplitude of the LHRH-secretory episodes modulate the pattern of LH and FSH secretion. Circulating inhibin and gonadal steroids influence the secretion of gonadotropins by acting on the both the hypothalamus and the pituitary.

Glucose homeostasis primarily depends on the balance between glucose production by the liver and glucose use by both insulin-dependent tissues (such as muscle and fat) and non-insulin dependent tissues (such as the brain).

The pancreas is a gland of both exocrine and endocrine functions. It is attached to the second and third portion of the duodenum on the right. The parts of the pancreas are the head, neck, and body of tail. Pancreas is supplied by splenic, gastroduodenal, and superior mesenteric arteries and drains into superior & inferior mesenteric veins. The major components of pancreatic exocrine function are acinar cells and ductal system. Pancreatic ductal system is the network of conduits that carry the exocrine secretion into the duodenum. The endocrine functions of pancreas only accounts for 2% of pancreatic mass.

If a patient has an insulin deficiency and excess level of glucagon, what happens?

He or she will have hyperglycemic disorders. Diabetes mellitus (DM) is a heterogenous group of hyperglycemic disorders. If the insulin deficiency is very severe, the beta cell abnormalities of pancreas cause ketoacidosis, hyperosmolar coma and other manifestation of catabolism.
[31] If the insulin level is very high secondary to insulin injections, insulinoma, or fasting, then hypoglycemia will occur and the patient may develop seizure if glucose level is too low. Diabetes mellitus is the leading cause of blindness in the United States.
[32] The serious long-term complications due to DM are DM retinopathy, DM neuropathy, DM neuropathy, and high risks for strokes, cataracts, heart attacks, obesity, and amputations.

Prolactin-growth hormone family-lactotrope

Prolactin is a pituitary hormone involved in the stimulation of milk production, reproduction, growth development, and water and salt regulation. Normal pituitary gland in lactotrope cells are small, polyhedral, and sparsely granulated with fine multiple cytoplasmic processes and a well-developed RER and Golgi complex. Human prolactin consists of 199 amino acids and has 3 intramolecular disulfide bonds. Only 16% of the amino acids of prolactin are homologous with those of GH. Prolactin-producing cells make up approximately 20% of pituitary. Prolactin circulates in blood predominantly in a monomeric form, although glycosylated forms of prolactin exist. Prolactin is synthesized by the fetal anterior pituitary from the fifth week gestation. Serum prolactin levels in the fetus remain low until approximately 26 weeks and rise to levels in excess up to 150 microgram/L at term.
[33]

Prolactin is an anterior pituitary hormone and is secreted in an episodic manner. The secretion is enhanced by prolactin releasing factors and is inhibited by dopamine. Dopamine acts by stimulating the lactotrope D2 receptor to inhibit adenylate cyclase and consequently to inhibit prolactin synthesis and prolactin release. Prolactin acts on prolactin receptors in multiple tissues, including breast, ovary, testis, liver, and prostate. The main site of prolactin is the mammary gland, and it is important in development of milk synthesis. During pregnancy and lactation, the physiological hyperprolactinemia and pathologic hyperprolactinemia are associated with suppression of hypothalamic-pituitary-gonadal axis.
[33] During sleep, decreased dopaminergic inhibition is likely involved and prolactin level increases.

Abnormalities of prolactin level excess or deficit?

Hyperprolactinemia is a frequent endocrine disorder with well-recognized harmful effects on the reproductive system and bone metabolism. A prolactinoma is the most common cause of hyperprolactinemia (60% of cases). It causes infertility and gynecomastia. Other causes include non-functioning pituitary adenoma and dopaminergic antagonist drugs (eg, phenothiazines, haloperidol, clozapine, metoclopramide, domperidone, methyldopa, cimetidine); primary hypothyroidism (thyrotrophin-releasing hormone stimulates the secretion of prolactin), or it may be idiopathic. Prolactin acts directly on the hypothalamus to reduce the amplitude and frequency of pulses of gonadotrophin-releasing hormone.

Besides prolactinomas, several drugs and disorders such as liver cirrhosis, renal failure, and hypothyroidism have been shown to cause hyperprolactinemia. In a recent study by Ress et al, hyperprolactinemia is not commonly found in patients with liver cirrhosis, but is mostly associated with intake of drugs or the presence of comorbidities known to potentially cause hyperprolactinemia. The authors therefore proposed that in contrast to prior studies, liver cirrhosis is not a common cause of hyperprolactinemia and that in the absence of comorbidities or drugs known to potentially increase prolactin levels, marked hyperprolactinemia needs further investigation in patients with liver cirrhosis.
[34]

Hormones involved in appetite regulation

Leptin

Leptin is an anorexigenic hormone, mainly is secreted from white adipocytes and serum levels of leptin correlate with adipose tissue mass. It is a product of "ob" gene and is a 167 amino acid peptide. Leptin acts on the satiety center of hypothalamus through specific receptors (ob-R) to restrict food intake and enhance energy expenditure.
[35]

Leptin plays a crucial role in the maintenance of body weight and glucose homeostasis through central and peripheral pathways, including regulation of insulin secretion by pancreatic cells. In young healthy subjects, circulating leptin levels show diurnal rhythm with highest levels during mid-sleep and the lowest levels during the day.
[36] In obese subjects, circulating leptin levels are increased, but the relative amplitude of their diurnal variation is decreased.
[36] The diurnal leptin variations of anorexia nervosa patients are abolished and leptin levels are low.
[37]

The prolonged total sleep deprivation results in a decreased amplitude of the 24-hour leptin rhythm.
[38] Leptin has been implicated in causing peripheral insulin resistance by attenuating insulin action, and perhaps insulin signaling, in various insulin-responsive cell types.

Ghrelin

Ghrelin is an organic hormone, secreted primary by stomach and the duodenum.
[39] Ghrelin also stimulate ACTH, prolactin and Growth hormone secretion The current data have been reported on the possible effects on ghrelin on sleep.
[40] Ghrelin level rises before each designated mealtime and it drops 1 hour after eating
[41] and it also rises during the first part of night suggesting the diurnal rhythm.
[42] Ghrelin levels increase following a diet induced weight loss and ghrelin levels decrease in young obese subjects compare to lean controls.
[43, 44]

In contrast, no difference was evidenced in middle-aged subjects between lean or obese subjects. Thus, the normal regulation of ghrelin levels by the energy balance state appears to be disrupted with aging. Partial sleep deprivation induced the increased levels of ghrelin and drops leptin levels. Sleep restriction is associated with an increased hunger, which was positively correlate a rise of ghrelin-to-leptin ratio.
[45] Thus, sleep deprivation and aging appear to induce endocrine alternation in energy balance state of ghrelin and leptin levels. The role of stem cell transplantation and its limitations are under investigation for various hormones.
[46]